We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice).
Genomic profiles of 628 NB samples analyzed by array-comparative genome hybridization (a-CGH) were re-examined to identify gene amplifications other them MYCN amplification.
In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway.
In the present study, we examined the concordance of droplet digital PCR (ddPCR, in combination with immunohistochemistry, IHC) with FISH for MYCN detection in a panel of formalin-fixed paraffin-embedded (FFPE) human neuroblastoma samples.
The tumor-suppressive miR-186 that is downregulated in neuroblastoma and in TGFβ-treated NK cells represses oncogenic proteins in neuroblastoma (MYCN and AURKA) and components of the TGFβ pathway.
We also discuss the subtype of retinoblastoma driven by the MYCN oncogene more commonly associated with neuroblastoma, and consider trilateral retinoblastoma, in which an intracranial tumor arises along with ocular tumors in patients with germline RB1 gene mutations.
This is the first report of a recurrence of congenital 4S neuroblastoma following resolution in which MYCN amplification is only detected in the recurrence.
The proposed prognostic cell risk score (pCRS) model we constructed can be an independent prognostic indicator for overall survival (OS) and event-free survival (EFS) (training: OS, HR 1.579, EFS, HR 1.563; validation: OS, HR 1.665, 3.848, EFS, HR 2.203, all <i>p</i>-values < 0.01) and only independent prognostic factor in <i>International Neuroblastoma Risk Group</i> high risk patients (HR 1.339, 3.631; <i>p</i>-value 1.76e-2, 3.71e-5), rather than MYCN amplification.
SIGNIFICANCE: This study presents a novel approach to drugging an amplified oncogene by showing that targeting gene amplification of <i>MYCN</i> suppresses MYCN expression and neuroblastoma growth.
Neuroblastoma (NB) is a widely diagnosed cancer in children, characterized by amplification of the gene encoding the MYCN transcription factor, which is highly predictive of poor clinical outcome and metastatic disease. microRNAs (a class of small non-coding RNAs) are regulated by MYCN transcription factor in neuroblastoma cells.
Further, pan-aurora kinase inhibitor (tozasertib) treatment not only induces cell-cycle arrest and suppresses cell proliferation, migration, and invasion ability in MYCN-amplified (MNA) neuroblastoma cell lines, but also inhibits tumor growth and prolongs animal survival in Th-MYCN transgenic mice.
In addition, this combination reduced the protein levels of MYCN proto-oncogene and nuclear factor kappa B, both of which are important for NB tumorigenesis and progression.
Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease.